Atherosclerosis and other peripheral vascular diseases are the major causes effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies.
Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called "normal" level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal" level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum" (or "ideal") value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as low density lipoprotein (LDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and partially as very low density lipoprotein (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and atherosclerosis with serum HDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increases with increasing levels of LDL and VLDL.
In CAD, generally "fatty streaks" in carotid, coronary and cerebral arteries, are found which are primarily free and esterified cholesterol. Miller et al, (Br. Med J., 282 (1981), 1741-1744) have shown that increase in HDL-particles may decrease the number of sites of stenosis in coronary arteries of humans, and high level of HDL-cholesterol may protect against the progression of atherosclerosis. Picardo et aL, (Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experiment that HDL is capable of removing cholesterol from cells. They suggest that HDL may deplete tissues of excess free cholesterol and transfer them to the liver (Macikinnon et al., J. Biol Chem. 261(1986), 2548-2552). Therefore, agents that increase HDL cholesterol would have therapeutic significance for the treatment of hypercholesterolernia and coronary heart diseases (CHD).
Obesity is a disease highly prevalent in affluent societies and in the developing world and which is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression has been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart idisease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
Diabetes and insulin resistance is yet another disease which severely effects the quality of life of a large population in the world. In insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75: 809-817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperisulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes melritus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X.
Hyperlipidemia is the primary cause of cardiovascular (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor super family. The gamma (.gamma.) isoform of PPAR (PPAR.gamma.) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (.alpha.) isoform of PPAR (PPAR.alpha.) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618-621). PPAR.alpha. agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that the hypolipidemic effect is enhanced when the molecule has both PPAR.alpha. and PPAR.gamma. agonist activity and are suggested to be useful for the treatment of syndrome X (WO 97/25042). Synergism between the insulin sensitizer (PPAR.gamma. agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma. (EP 0 753 298).
It is known that PPAR.gamma. plays an important role in adipocyte differentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, (1994) 79, 1147-1156) including cell cycle withdrawal. PPAR.gamma. is consistently expressed in certain cells and activation of this nuclear receptor with PPAR.gamma. agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of cancer expression of prostate cancer tissue (Cancer Research (1998) 58, 3344-3352). This would be useful in the treatment of certain types of cancer, which expresses PPAR.gamma. and could leading to a quite nontoxic chemotherapy.
Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications. Kallen et al (Proc. Natl. Acad. Sci., (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to their PPAR agonist expression and therefore lower plasm leptin concentrations. However, it has been recently disclosed that compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
A few .beta.-aryl-.alpha.-hydroxy propionic acids, their derivatives, and their analogs have been reported to be useful in the treatment of hyperglycernia and hypercholesterolemia. Some of such compounds described in the prior art are outlined below:
i) U.S. Pat. No. 5,306,726; and WO 91/19702 disclose several 3-aryl-2-hydroxy-propionic acid derivatives of general formula (II a) and (II b) as hypolipidemic and hypoglycemic agents. ##STR3## PA1 ii) International Patent Applications, WO 95/03038 and WO 96/04260 disclose compounds of formula (II e) ##STR5## PA1 wherein R.sup.a represents 2-benzoxazolyl or 2-pyridyl and R.sup.b represents CF.sub.3, CH.sub.2 OCH.sub.3 or CH.sub.3. A typical example is (S)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trif luoroethoxy)propanoic acid (II f). ##STR6## PA1 iii) International Patent Application Nos. WO 94/13650, WO 94/01420 and WO 95/17394 disclose the compounds of general formula (II g) EQU A.sup.1 --X--(CH.sub.2).sub.n --O--A.sup.2 --A.sup.3 --Y.R.sup.2 (II g) PA1 wherein A.sup.1 represent aromatic heterocycle, A.sup.2 represents substituted benzene ring and A.sup.3 represents moiety of formula (CH.sub.2).sub.m --CH--(OR.sup.1), wherein R.sup.1 represents alkyl groups, m is an integer of the range of 1-5; X represents substituted or unsubstituted N; and Y represents C.dbd.O or C.dbd.S. R.sup.2 represents OR.sup.3 where R.sup.3 may be hydrogen, alkyl, aralkyl, or aryl group; and n represents an integer in the range of 2-6. An example of these compounds is shown in formula (II h) ##STR7## PA1 Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2-p ropenoate; PA1 (.+-.)-Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]prop anoate; PA1 (+)-Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]prop anoate; PA1 (-)-Ethyl 2-ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]prop anoate; PA1 (.+-.)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]pheny l]propanoic acid and its salts; PA1 [2R, N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]pheny l]-N-(2-hydroxy-1-phenylethyl)propanamide; PA1 [2S, N(1S)]2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]pheny l]-N-(2-hydroxy-1-phenylthyl)propanamide; PA1 (+)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-dihydro -1,3-benzoxazin-3-yl]ethoxy]phenyl]propanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[2-[4-oxo-3,4-diydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]pr opanoic acid and its salts; PA1 (.+-.)-Ethyl 2-phenoxy-3-[4-[2-[4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phenyl]-2- propenoate; PA1 (.+-.)-Ethyl 2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethox y]phenyl]propanoate; PA1 (+)-Ethyl 2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]-etho xy]phenyl]propanoate; PA1 (-)-Ethyl 2-ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethox y]phenyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl ]ethoxy]phenyl]propanoic acid and its salts; PA1 (+)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]et hoxy]phenyl]propanoic acid and salts; PA1 (-)-2-Ethoxy-3-[4-[2-[2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]et hoxy]phenyl]propanoic acid and its salts; PA1 (.+-.)-Methyl 2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propa noate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propa noate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]propa noate; PA1 (.+-.)2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl] propanoic acid and its salts; PA1 (+)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]pr opanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[[4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phenyl]pr opanoic acid and its salts; PA1 (.+-.)-Methyl 2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]pro panoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]pro panoate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxyl]phenyl]pr opanoate; PA1 (.+-.)2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tethydro-2-quinazolinyl]methoxy]phenyl] propanoic acid; PA1 (+)-2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl] propanoic acid; PA1 (-)-2-Ethoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl] propanoic acid; PA1 (.+-.)-Methyl 2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]p henyl]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]p henyl]propanoate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxylp henyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-(4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]met hoxy]phenyl]propanoic acid and its salts; PA1 (.+-.)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetahydro-2-quinazolinyl]meth oxy]phenyl]propanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methox y]phenyl]propanoic acid and its salts; PA1 (.+-.)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro -2-quinazolinyl]methoxy]phenyl ]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]p henyl]propanoate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]p henyl]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phe nyl]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phe nyl]propanoate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy]phe nyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]metho xy]phenyl]propanoic acid and its salts; PA1 (+)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy] phenyl]propanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[[3-methyl-4-oxo-3,4-dihydro-1,3-benzoxazin-2-yl]methoxy] phenyl]propanoic acid and its salts; PA1 (.+-.)-Methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]ph enyl]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo1,2,3,4-tetrahydro-2quiazolinyl]methoxy]pheny l]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]ph enyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]meth oxy]phenyl]propanoic acid and its salts; PA1 (+)-2-Ethoxy-3-[4-[[3-ethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy ]phenyl]propanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[[3-ethy-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyl]propanoic acid and its salts; PA1 (.+-.)-Methyl-2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quina zolinyl]methoxy]phenyl ]propanoate; PA1 (+)-Methyl 2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]metho xy]phenyl]propanoate; PA1 (-)-Methyl 2-ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]metho xy]phenyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl ]methoxy]phenyl]propanoic acid and salts; PA1 (+)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-4-tetrahydro-2-quinazolinyl] methoxy]phenyl]propanoic acid and salts; PA1 (-)-2-Ethoxy-3-[4-[[1,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]me thoxy]phenyl]propanoic acid and salts; PA1 (.+-.)-Methyl 2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]pr opanoate; PA1 (+)-Methyl 2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]pr opanoate; PA1 (-)-Methyl 2-phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl]pr opanoate; PA1 (.+-.)-2-Phenoxy-3-[4-[[4-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl] propanoic acid and its salts; PA1 (+)-2-Phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl ]propanoic acid and its salts; PA1 (-)-2-Phenoxy-3-[4-[[4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl ]propanoic acid and its salts; PA1 (.+-.)-Methyl 2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyl]propanoate; PA1 (+)-Methyl 2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyl]propanoate; PA1 (-)-Methyl 2-phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy] phenyl]propanoate; PA1 (.+-.)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]me thoxy]phenyl]propanoic acid and its salts; PA1 (+)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]metho xy]phenyl]propanoic acid and its salts; PA1 (-)-2-Phenoxy-3-[4-[[6-chloro-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]metho xy]phenyl]propanoic acid and its salts; PA1 (.+-.)-Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phe nyl]propanoate; PA1 (+)-Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phe nyl]propanoate; PA1 (-)-Ethyl 2-ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]phe nyl]propanoate; PA1 (.+-.)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]etho xy]propanoic acid and its salts; PA1 (+)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy] propanoic acid and its salts; PA1 (-)-2-Ethoxy-3-[4-[2-[6-nitro-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy] phenyl]propanoic acid and its salts; PA1 (.+-.)-Ethyl 2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]ph enyl]propanoate; PA1 (+)-Ethyl 2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]ph enyl]propanoate, PA1 (-)-Ethyl 2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy]ph enyl]propanoate; PA1 (.+-.)-2-ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]eth oxy]phenyl]propanoic acid and it s salts; PA1 (+)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy ]phenyl]propanoic acid and its salts; and PA1 (-)-2-Ethoxy-3-[4-[2-[6-acetyl-4-oxo-3,4-dihydro-1,3-benzoxazin-3-yl]ethoxy ]phenyl]propanoic acid and its salts;
Examples of these compounds are shown in formula (II c) and (II d) ##STR4##